Garth Hall, Biological Sciences, Biomedical Engineering

Garth Hall, Biological Sciences, Biomedical Engineering

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Research Interest

My main long term research focus has been on the generation and maintenance of neuronal form, and related aspects of neuronal cell biology. In particular, I am interested in how neurons generate and maintain cellular polarity and the role that neuronal polarity disruption may play in a) the recovery of axonal function after axotomy and the cytopathogenesis of Alzheimer’s disease and related conditions. In recent years, I have focused on the role played by the cytoskeleton-associated protein tau in neurodegenerative tauopathies, and have become increasingly interested in the possible role of tau abnormalities in mediating interneuronal aspects of these diseases. This has led to current interests in tau-NF interactions and synergistic interactions between tau, PrP and alpha synuclein and their possible involvement in endocytosis/secretion of tau in AD.

My current interests are outgrowths of my thesis research with Dr. Melvin Cohen at Yale in the 1980s, where I discovered and characterized axotomy-induced neuronal polarity loss in a subset of giant Muller neurons (ABCs) in the hindbrain of the ammocoete sea lamprey1-5. I became interested in the possibility that axonal degeneration6 and polarity loss7-8 might be central events in the pathogenesis of Alzheimer’s Disease9, and took a postdoctoral position with Dr. Kosik, with whom I used the ABC axotomy model to study the interaction of axotomy and endogenous cytoskeletal elements10-13. I have since maintained my interest in the cellular response to axotomy, with a particular interest in the role of neurofilaments in maintaining axonal form14-18. However, my major research focus has since been on the role of the cytoskeleton in disease pathogenesis as described below.

I have used the lamprey ABC system as a model to study the cytopathology of human tau since 1994, and published a study of neurodegeneration induced by tau overexpression via plasmid injection into ABCs in 199719. This was the first study to demonstrate tau-induced cytotoxicity in any system, and its success (following years of unsuccessful attempts to model tau-induced degeneration in cell culture) highlighted the need for in situ modeling approaches to tauopathy. In 1997 I moved to U. Mass. Lowell and devoted the next decade to characterizing the lamprey tauopathy model19-26 and examining the effects of anti-aggregation agents on tau-induced neurotoxicity and intracellular turnover27. During this time, work in my laboratory showed that extracellular tau deposits derived from tau-expressing ABCs can accumulate during the course of degeneration19, 23 and that tau clearance via secretion is associated with the neuroprotective effects of a low molecular weight anti-aggregation agent (NNI3)27. The significance of this last finding (i.e. that human tau can be secreted from non-degenerating, fully differentiated neurons in situ) has recently become our major recent research focus.

My current research focuses on the integration of tau pathobiology at the cellular level with intercellular aspects of tauopathy pathogenesis. Since tau is universally known as an exclusively intracellular protein which is never secreted to the extracellular space, it has been assumed until very recently that tau protein cannot be secreted and thus can only reach the CSF once the neurons that synthesized it have died. We recently showed that tau protein is secreted by viable neurons in both cell culture and in situ (i.e. lamprey ABC) models of AD without the aid of anti-aggregation agents such as NNI328, and that tau secretion requires the N terminus28 and is significantly inhibited by the presence of the N terminal exon 2 sequence29, confirming that tau release is due to an active biological process. This work challenged the assumption that tau release must be passive and was initially difficult to publish. However, our findings together with congruent findings in other systems-(i.e. that tau can be taken up into adjacent neurons in culture30 and can be transferred between neurons in a mouse model31) have kindled interest in interneuronal tau movement in the AD/tauopathy research community, since it is now becoming clear that tau secretion may have important ramifications for the development of AD diagnostics and possibly for our overall understanding of the role of tau pathobiology in human disease. We are currently characterizing the tau secretion mechanism in more detail using both lamprey and cell culture models and have begun to extend this work to human brain and CSF samples from AD patients, using the absence of exon 2 secreted tau has a specific biomarker to ask whether tau secretion plays a role in the genesis of elevated CSF-tau in AD32-33.